Mitochondrial calcium cycling in neuronal function and neurodegeneration

Abstract

Mitochondria are essential for proper cellular function through their critical roles in ATP synthesis, reactive oxygen species production, calcium (Ca²⁺) buffering, and apoptotic signaling. In neurons, Ca²⁺ buffering is particularly important as it helps to shape Ca²⁺ signals and to regulate numerous Ca²⁺-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal toxicity. Over the past decade, identification of the mitochondrial Ca²⁺ uniporter (MCU) and other molecular components of mitochondrial Ca²⁺ transport has provided insight into the roles that mitochondrial Ca²⁺ regulation plays in neuronal function in health and disease. In this review, we discuss the many roles of mitochondrial Ca²⁺ uptake and release mechanisms in normal neuronal function and highlight new insights into the Ca²⁺-dependent mechanisms that drive mitochondrial dysfunction in neurologic diseases including epilepsy, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We also consider how targeting Ca²⁺ uptake and release mechanisms could facilitate the development of novel therapeutic strategies for neurological diseases.

Keywords: MCU; calcium; mitochondria; neurodegeneration; neuronal calcium homeostasis.